Medical Device Link.

The IVD Directive was formally adopted by the EU's Council of Ministers on October 5, 1998, and was published in the Official Journal of European Communities on December 7, 1998.¹ The competent authorities in the various member states are responsible for ensuring that the requirements of the directive are carried out. Underlying all three of the EU's directives on medical devices are these general principles.

This article is the first of a three-part series looking at the key requirements that manufacturers of IVDs must satisfy in order to market their products in the EU after December 7, 2003, when the CE marking requirements of the directive take full effect.

The IVD Directive defines an in vitro diagnostic medical device as

This definition includes specimen receptacles, which the directive further defines as "those devices, whether vacuum-type or not, specifically intended by their manufacturers for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination."

According to the directive, accessories are not in themselves IVDs. The directive defines an accessory as "an article which, whilst not being an in vitro diagnostic medical device, is intended specifically by its manufacturer to be used together with a device to enable that device to be used in accordance with its intended purpose."

Also excluded are products for general laboratory use, which the directive says are not IVDs "unless such products, in view of their characteristics, are specifically intended by their manufacturer to be used for in vitro diagnostic examination."

Classification. The directive divides IVD devices into four categories according to their intended use and the risks to public health or patient treatment in the event a product should fail to perform as intended.

The Annex II lists include specific products whose accuracy is essential for medical practice and for which any malfunction would be likely to seriously endanger health. The last category represents the great majority of IVDs; they involve no direct risk to the tested person because they are used primarily by properly trained professionals. Furthermore, the results of such analyses may often be confirmed by other means.

The IVD Directive defines manufacturer as "the natural or legal person with responsibility for the design, manufacture, packaging, and labeling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party."

Manufacturers' obligations under the IVD Directive also apply to kit manufacturers and refurbishers. Without defining a particular term for such companies, the directive incorporates them in describing "the natural or legal person who assembles, packages, processes, fully refurbishes, or labels one or more ready-made products or assigns to them their intended purpose as devices with a view to their being placed on the market under his own name."

Registration. The manufacturer must register itself and each of its products with the regulatory authority of the member state in which it is located. If the manufacturer is located outside the EU, the registration should be filed by the manufacturer's authorized representative, which the directive defines as "any natural or legal person established in the community who, explicitly designated by the manufacturer, acts and may be addressed by authorities and bodies in the community instead of the manufacturer with regard to the latter's obligations." The documents of registration must include the following information.

The EU Database. The EU is establishing a regulatory database accessible only to member states and the European Commission. Member states will load into the database the information they receive from manufacturers and notified bodies. When completed, the database will contain information relating to all devices available in the EU, including the following.

Although all three of the EU's directives on medical products have come into force, the regulatory database is not yet operational. Until it becomes operational, manufacturers must register separately with each member state when they place a device on the market in their territory.

The IVD Directive specifically distinguishes between the marketing and the use of IVD products. Placing on the market means "the first making available in return for payment or free of charge of a device other than a device intended for performance evaluation with a view to distribution and/or use on the community market, regardless of whether it is new or fully refurbished." Putting into service means "the stage at which a device has been made available to the final user as being ready for use on the community market for the first time for its intended purpose." This distinction is important with regard to the final implementation of the CE marking requirements of the directive. Products sold prior to December 8, 2003, are not required to bear the CE mark of conformity; however, such products must be put into service within two years of that date.

CE Marking. Manufacturers indicate that a product complies with the terms of the IVD Directive by affixing the CE mark of conformity. Products whose compliance must be certified by a notified body carry the CE mark in combination with the identification number of the notified body.

Application of the CE mark represents a declaration by the manufacturer that the product meets all applicable provisions of the relevant legislation, including those relating to safety, and has been subjected to the requisite conformity assessment procedures. Products bearing the CE mark may be freely marketed anywhere in the European Union; manufacturers are not required to comply with national schemes that might impose additional requirements.

Essential Requirements. Annex I of the directive specifies the essential requirements that IVDs must satisfy before they may be CE marked and placed on the market. This means that the manufacturer must demonstrate that the IVD under consideration does not compromise the health and safety of patients and users, and is designed and manufactured in such a way that it is suitable for the stated medical purpose, taking account of the generally acknowledged state of the art.

The IVDs under consideration must be able to achieve their specified performance, where appropriate, in terms of analytical and diagnostic sensitivity, analytical and diagnostic specificity, accuracy, repeatability, reproducibility, control of known relevant interference, and limits of detection.

Not all of the essential requirements apply to all products. It is the responsibility of the manufacturer to assess which requirements are considered appropriate for a particular product. Following are a few of the key provisions outlined as essential requirements.

Manufacturers must ensure that the values assigned to calibrators and control materials are traceable through available reference measurement procedures or available reference materials to standards of a higher metrological order.²

The manufacturer has to show that the IVD under consideration has been designed, manufactured, and packaged in such a way that its characteristics and performance during use will not be adversely affected when it is stored and transported according to instructions.

Risks related to the use of a diagnostic device must be identified, and the manufacturer must demonstrate the acceptability of such risks by means of a risk analysis.³ In mediating risks, the design and manufacturing solutions adopted by the manufacturer must conform to safety principles, taking account of the generally acknowledged state of the art. The manufacturer must eliminate or reduce risks as far as possible and, where appropriate, take adequate protection measures in relation to risks that cannot be eliminated. Manufacturers must inform users of any residual risks due to shortcomings of the protection measures adopted.

Because of the importance of ensuring that diagnostic tests are performed correctly, the directive emphasizes the adequacy of labeling information and instructions for use, both for devices intended for professional use and for self-tests intended for use by laypersons.

Technical Documentation. The manufacturer must prepare technical documentation sufficient to enable assessment of the conformity of the product with the requirements of the IVD Directive. The specific requirements for such documentation depend on the conformity assessment route selected for the product, as defined in the annexes of the IVD Directive. (Procedures for conformity assessment will be discussed in the second installment of this article.)

Vigilance. Each manufacturer is required to maintain a systematic procedure for reviewing postproduction experiences and implementing any necessary corrective actions. The manufacturer must also maintain a vigilance system for notifying regulatory authorities of any incident that results in, or could have resulted in, death or serious injury, or a systematic recall of a device in order to prevent death or serious injury.

Safeguard Clause. Where it is found that a device, when used for its intended purpose, may compromise the health and safety of patients, users, or other persons, the member state in which the device is sold may take action to withdraw the device from its territory and inform the European Commission and other member states of its action. Member states have the power to restrict or prohibit the placing on the market of devices with wrongly affixed CE marks.

For some routes to conformity assessment the IVD Directive requires the involvement of third-party review and testing organizations—the so-called notified bodies. Usually, the competent authorities of each member state assess the technical competence of organizations that apply to become notified bodies, and decide whether they are competent and capable of undertaking the necessary responsibilities.

The designation of a notified body is formalized when the member state sends an official notification of that designation to the European Commission (hence the term notified body). The commission assigns each notified body an identification number that remains the same if the organization is later notified for other EU directives.

Notified bodies participate in premarket conformity assessment procedures (including assessment of a manufacturer's quality systems). They are distinct from the public authorities (national, regional, and local) that are responsible for postmarket surveillance over products.

Competence Criteria. Notified bodies are expected to operate in a competent, nondiscriminatory, transparent, neutral, independent, and impartial manner when carrying out their assigned tasks. The IVD Directive sets out the following general criteria for assessing the competence of a prospective notified body.

Duties of Notified Bodies. Under the IVD Directive, notified bodies can perform conformity assessment for IVD products and related quality systems (as outlined in Article 9 and Annexes III, IV, V, VI, and VII). A national competent authority may designate a notified body for a limited scope of device families or annexes. Notified bodies remain under the surveillance of their national authorities, who may withdraw or modify the notification if the conditions of notification are no longer met.

Notified bodies can offer the services for which they are notified to any manufacturer, whether based in the EU or in another country. The notified body may carry out its activities using either its home resources or the staff of its foreign offices.

Notified bodies have obligations and responsibilities in relation to the suspension or withdrawal of certificates, requests addressed to manufacturers to take corrective measures, and corresponding reports to competent authorities. On request, they must also make available all additional relevant information.

The IVD Directive went into force on June 7, 2000. Since that time, it has been possible for manufacturers to certify and CE mark IVD products under the terms of the directive.

However, during the transition period that lasts until December 7, 2003, manufacturers can continue to place on the market products that meet only the requirements of existing national laws. At the end of the transition period—that is, beginning December 8, 2003—it will be mandatory for manufacturers to comply with the CE marking requirements of the IVD Directive.

The next installment of this article will look at the routes to product conformity assessment available to manufacturers under the terms of the IVD Directive.

The third installment will examine the common technical specifications required of Annex II products.